PROJECT SUMMARY During periods of wakefulness, there is substantial variability in the capacity to detect and discriminate among sensory stimuli and form behaviorally relevant motor actions. This variability in perceptual decision making is due in large part to constant fluctuations in the spatiotemporal characteristics of neuronal network activity in the (neo)cortex. These continuous changes in cortical state substantially affect sensory-evoked cortical responses and, ultimately, perceptually guided behavior. Thus, a comprehensive understanding of cortical sensory processing must take cortical state fluctuations into account and explain their underlying mechanistic basis. Furthermore, it is crucial to understand how different brain structures control cortical state in order to understand how these structures might be impaired in neurological and psychiatric diseases associated with dysfunctional sensory processing. There are two significant gaps in our knowledge about the relation between different cortical states and cortical sensory processing: 1.) The nature of the cortical state that enables optimal sensory processing is unclear, and 2.) Details about the roles of neuromodulatory structures in optimal perceptually guided behavior are scarce. The first deficiency in our knowledge is due to the relative coarseness of the quantification of ?state? in the literature ? primarily stillness versus locomotion. The second deficiency is due to the lack of studies monitoring and manipulating the activity of neuromodulatory pathways during perceptual decision making tasks. My proposal will address these issues. I will train freely moving, head-fixed mice on a novel visual stimulus detection task, and determine the optimal cortical state for task performance by using pupillometry to quantify the spectrum of cortical states. Using this task as a paradigm of perceptually guided behavior, I will then study the neural correlates of optimal task performance in primary visual cortex, assess the state-dependent neuronal activity in locus coeruleus (the source of noradrenergic projections to cortex), and dissect the causal role of locus coeruleus activity in mediating optimal task performance. Overall, my research will shed new light on the mechanisms of state-dependent cortical sensory processing, and perhaps provide novel insight into how optimal sensory processing is impaired in certain neurological and psychiatric disorders.